tbuckley/cabot-search huggingface dataset:
P1290: UPFRONT ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION CAN PROVIDE SURVIVAL BENEFIT VERSUS HYPOMETHYLATING AGENT IN MYELODYSPLASTIC SYNDROME WITH INCREASED BLASTS I (MDS-IBI)
Authors: MA Runzhi, Sisi Zhen, Jieru Wang, LI Liu, Erlie Jiang, Mingzhe Han, Zefeng Xu, Zhijian Xiao, Sizhou Feng
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Myelodysplastic syndrome (MDS) is a group of clonal disorders of hematopoietic stem cell. Survival would be significantly shortened if excessive blasts appear in marrow or the periphery. As disease progression accelerating, about 25% of MDS-IB1 and 33% of MDS-IB2 patients were reported to finally transformed into leukemia. Currently, allogeneic stem-cell transplantation (Allo-HSCT) still remains the only curable treatment accompanied with risk of therapy related mortality and decline of life quality. Decitabine (DAC), an of DNA methylation, was also reported to exhibit benefit in treatment of MDS. Thus, comparative studies with Allo-HSCT are needed. Aims: To retrospectively compare response of upfront allogeneic HSCT with hypomethylating agent (DAC in 87.5% of the group) therapy according to stem-cell donor availability in patients with MDS-IB1. Methods: We retrospectively reviewed 103 patients with primary MDS patients who were evaluated and received treatment in our center between August 2011 and August 2020. Overall survival (OS), event-free survival (EFS), non-relapse mortality (NRM) and cumulative rate of relapse or progression (CIR) at 1 year was calculated according to treatment arm. Cox regression analyses with allo-HSCT as time-dependent covariate (Mantel-Byar approach) were performed. Results: One-hundred and three patients with a median age of 49 years were included. Allo-HSCT was performed in 61.2% (n=63) and the rest 38.8% (n=40) received continuous HMA. The median follow-up time for surviving patients was 30.4 months (range: 3.2-122.1 months). In the entire cohort, non-relapse mortality rate at 1 year was significantly higher in the allo-HSCT group compared with HMA group (14.3% vs. 2.5%, P=0.008), and the cumulative incidence of relapse and progression at 1 year was significantly lower (1.6% vs. 45.5%, P<0.001). After matching with propensity-score, the overall survival rate at 3 years was 77.8% in the allo-HSCT group compared with 43.5% in the HMA group with a significant difference by Cox-regression considered allo-HSCT as time-dependent covariate (P=0.045), and event-free survival rate at 3 years was higher in allo-HSCT patients (73.4%) compared with HMA group (20.6%; P=0.001). Summary/Conclusion: In MDS-IB1 patients, allogeneic HSCT resulted in significantly prolonged overall survival and event-free survival compared with continuous HMA therapy. MDS-IB1 patients may be benefit from an earlier upfront allo-HSCT plan.Figure legend: (A-B) Simon-Makuch curve for (A) OS and (B) EFS in the entire cohort after HMA or HSCT; (C-D) Simon-Makuch curve for (C) OS and (D) EFS in matched cohort after HMA or HSCT. Keywords: Allogeneic hematopoietic stem cell transplant, Myelodysplastic syndrome
P1410: EFFICACY OBSERVATION OF A SECOND INFUSION OF BCMA-CAR-T CELLS IN PATIENTS WITH REFRACTORY/RELAPSED MULTIPLE MYELOMA
Authors: Yi Wang, Ben Niu, Limin Hou, Ding Zhang, Qiuying Gao, Hui Wang, Ying Gao, Yudi Miao, Xinhui Zhai, Ying Guo, Weihua Zhang, Xingli Ru, Yi Zhang
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Chimeric antigen receptor (CAR) T-cell therapy has exhibited remarkable clinical efficacy in the treatment of relapsed/refractory multiple myeloma (R/RMM), and BCMA-targeted CAR-T cell therapy for R/RMM can achieve an effective rate of more than 90%, with more than 70% of patients obtaining complete response (CR).However, even among patients with CR, relapse and progression of the disease may still occur, and currently there are few reports on the effectiveness of a second CAR-T cell infusion with the same target after progression of disease. Aims: To preliminarily analyze the adverse reactions and clinical efficacy of receiving a second BCMA-targeted CAR-T cell infusion for R/RMM. Methods: The adverse reactions, clinical efficacy and factors affecting the clinical efficacy of a second (including a third) CAR-T cell infusion of R/RMM in the Department of Hematology of Shaanxi Provincial People’s Hospital performed from March 2021 to January 2022 were retrospectively analyzed, and the cut-off time of observation period was at the death of patient or February 26, 2023. Results: A total of 24 patients with R/RMM [males vs. females (13 vs. 11), median age of 57 years (44 years –70 years)] who received a second (including a third) BCMA-CAT-T cell infusion were included in this study, of which 70.8% (17/24) were type IgG, 16.7% (4/24) were type IgD, 4.2%(1/24) was type light-chain, and 8.3% (2/24) were type IgA. For the time from the first BCMA-CAT-T cell therapy, 45.8% (11/24) of the patients were more than 12 months and 54.2% (13/24) were less than 12 months. 54.2% (13/24) of the patients were converted the murine CAR-T to human CAR-T, and 45.8% of the patients received the same humanized infusion. 83.3% (20/24) of the patients received only one CAR-T cell infusion before, and 16.7% (4/24) of the patients received twice in the past. After the BCMA-CAR-T infusion, 58.3 % (14/24) of patients had cytokine release syndrome (CRS), of which 50% (12/24) had grade 1 CRS, 8.3% (2/24) had grade 2 CRS, and only 4.2% (1/24) had grade 1 central nervous system reaction. The median observation time was 5 months (range: 1-18 months). The overall response rate (ORR) was 83.3 % (20/24), among which，41.6% of the patients achieved complete response (CR), 16.7% (4/24) achieved very good partial response (VGPR), and 25% (6/24) achieved partial response (PR). 25% (6/24) of the patients died during the observation period, and the overall survival rate at 12 months was 51.8 %. Summary/Conclusion: The patients with R/RMM who had received BCMA-CAR-T infusion and afterwards showed progressive disease or relapse, could receive a second BCMA-CAR-T therapy. Keywords: CAR-T, Multiple myeloma
P447: DECIPHERING THE MITOPHAGY RECEPTOR NETWORK IDENTIFIES A CRUCIAL ROLE FOR OPTINEURIN IN ACUTE MYELOID LEUKEMIA
Authors: Laura Meyer, Sebastian Koschade, Jonas Vischedyk, Marlyn Thölken, Andrea Gubas, Martin Wegner, Marion Basoglu, Stefan Knapp, Manuel Kaulich, Stefan Eimer, Shabnam Shaid, Christian Brandts
Journal: HemaSphere (2023)

Background: The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and, thereby, for disease maintenance and progression in acute myeloid leukemia (AML). Mitophagy is orchestrated by a variety of mitophagy receptors whose interplay is not well understood. Aims: We intended to systematically investigate the molecular mechanisms of mitophagy in AML and identify critical non-redundant components of the mitophagy receptor network required for leukemia maintenance and progression. Methods: We established a multiplexed CRISPR/Cas9 screen targeting mitophagy receptors and their pairwise combinations to elucidate redundancies and gain a deeper understanding of the functional interactome governing mitophagy in AML. Follow-up in vitro studies utilizing clonogenic assays, flow cytometry, fluorescence microscopy, transmission electron microscopy, immunoblotting, metabolic profiling, genetic manipulations with shRNA & CRISPR/Cas9 techniques as well as in vivo studies on syngeneic murine AML models with genetic or pharmacologic impairment of mitophagy were performed. Results: CRISPR/Cas9 experiments with a multiplexed gRNA library targeting all possible combinations of mitophagy receptors in AML cells constitutively expressing a mitophagy receptor (mt-mKeima) mapped the functional interactome of mitophagy receptors in AML. This pinpointed OPTN as a critical and independent mitophagy receptor and we subsequently characterized its unique role in both murine and human AML. Knockdown and overexpression experiments as well as rescue experiments reconstituting autophagy-deficient mutants or wild-type OPTN demonstrated that OPTN expression is rate-limiting for mitophagy and AML cell proliferation. Loss of OPTN delayed leukemia development in a MN1-driven murine transplantation model. Mechanistically, we found broadly impaired mitochondrial respiration and function with increased mitochondrial ROS upon loss of OPTN. Exogeneous addition of the ROS scavenger N-acetylcystein rescued the impaired proliferation of OPTN-deficient cells. Summary/Conclusion: Our results decipher the mitophagy receptor network in AML for both ubiquitin-dependent and receptor-mediated mitophagy, identify OPTN as a non-redundant tool to study mitophagy in the context of leukemia and suggest OPTN inhibition as an attractive therapeutic strategy in AML. Keywords: AML, Acute myeloid leukemia
P1625: CLINICAL AND LABORATORY CHARACTERISTICS OF ADULT PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA IN EASTERN AUSTRIA
Authors: Jasmin Rast, Theresa Schramm, Dino Mehic, Barbara Dixer, Michael Fillitz, Ingrid Pabinger, Cihan Ay, Johanna Gebhart
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Primary immune thrombocytopenia (ITP) is a rare acquired autoimmune disease, characterized through isolated thrombocytopenia (<100 x109/L) associated with an increased bleeding risk but also a paradoxically increased risk for thromboembolic events. Aims: Detailed clinical data on adult patients with primary ITP are scarce, due to the rarity of primary ITP. The Vienna ITP biobank on adult patients with primary ITP aims to capture longitudinal clinical data to further characterize ITP patients in Eastern Austria. Methods: The Vienna ITP biobank is an ongoing biobank study conducted at two hematological centers in Eastern Austria (Medical University of Vienna and Hanusch Hospital Vienna) and prospectively collects data of patients diagnosed with primary ITP (EC 1843/2016). Patient recruitment started in 2016 and is ongoing. Patients with primary ITP older than 18 years and with a platelet count of ≤150 x109/L in case of no ITP-specific treatment are included in the ITP Biobank. Active neoplastic disease, secondary/hereditary thrombocytopenia, secondary ITP or a platelet count >150 G/L without treatment are exclusion criteria. Blood for laboratory analyses is sampled and the individual medical and bleeding history of each patient is recorded at each visit. Bleeding severity is assessed using the ITP ISTH bleeding assessment tool (SMOG BS) and Vicenza BS. Results: Of 168 included patients, 2 withdrew consent, 5 turned out as EDTA-dependent pseudothrombocytopenia directly after patient inclusion and in 4 patients were uncovered as secondary ITP. Thus, the study cohort comprises a total number of 157 patients. Patients’ and ITP related characteristics are shown in Tables 1 In total, 39 patients (24.8%) had acute, 13 (8.3%) persistent and 105 (66.8%) chronic ITP at study inclusion. The majority of patients were female, and the mean age was 45.0 years. Almost half of the patients were under ITP treatment at the time of recruitment and 15 (9.5%) were splenectomized. The median (range) bleeding score was 1.0 (0.0-4.0), 32 patients (20.4%) had no bleeding at study inclusion. Anti-platelet antibodies were detected in 52 out of 125 patients with available measurements (41.6%), most of them directed against GP IIb/IIIa. Summary/Conclusion: Our cohort of ITP patients shows typical characteristics in respect to clinical and laboratory factors such as age distribution, female predominance, or antibody positivity. The in-depth clinical characterization of primary ITP patients of Eastern Austria in the Vienna ITP biobank will facilitate research projects in the future. Sponsor: The biobank from which this data derives is supported by Novartis, Swedish Orphan Biovitrum (SOBI), MedMedia Verlag und Mediaservice GmbH and AMGEN GmbHKeywords: Clinical data, Chronic ITP, Anti-platelet antibody, ITP
Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models
Authors: Debashis Dutta, Malabendu Jana, Ramesh Kumar Paidi, Moumita Majumder, Sumita Raha, Sridevi Dasarathy, Kalipada Pahan
Journal: Journal of Clinical Investigation (2023)

Glial activation and inflammation coincide with neurofibrillary tangle (NFT) formation in neurons. However, the mechanism behind the interaction between tau fibrils and glia is poorly understood. Here, we found that tau preformed fibrils (PFFs) caused induction of inflammation in microglia by specifically activating the TLR2/MyD88, but not the TLR4/MyD88, pathway. Accordingly, the WT TLR2-interacting domain of MyD88 (wtTIDM) peptide inhibited tau PFF-induced activation of the TLR2/MyD88/NF-κB pathway, resulting in reduced inflammation. Nasal administration of wtTIDM in P301S tau-expressing PS19 mice was found to inhibit gliosis and inflammatory markers, as well as to reduce pathogenic tau in the hippocampus, resulting in improved cognitive behavior in PS19 mice. The inhibitory effect of wtTIDM on tau pathology was absent in PS19 mice lacking TLR2, reinforcing the essential involvement of TLR2 in wtTIDM-mediated effects in vivo. Studying the mechanism further, we found that the tau promoter harbored a potential NF-κB-binding site and that proinflammatory molecules increased transcription of tau in neurons via NF-κB. These results suggest that tau-induced neuroinflammation and neuropathology require TLR2 and that neuroinflammation directly upregulates tau in neurons via NF-κB, highlighting a direct connection between inflammation and tauopathy.
P1272: DEFIBROTIDE IMPACT ON THE ACUTE GRAFT-VERSUS-HOST DISEASE INCIDENCE IN PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS.
Authors: Domenica Squillaci, Annalisa Marcuzzi, Erika Rimondi, Daniela Nistico’, Antimo Tessitore, Guglielmo Riccio, Egidio Barbi, Davide Zanon, Natalia Maximova
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has been insufficiently studied. Aims: The aim of this study was to assess the impact of defibrotide on the incidence and severity of aGVHD in a population of pediatric patients undergoing an allo-HSCT. Methods: Ninety-one pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the Defibrotide Group and the Control Group. Results: The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the Control Group. This advantage was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD (Figure 1). Moreover, the Defibrotide Group has recorded no sinusoidal obstruction syndrome (SOS)/veno-occlusive disease. The pro-inflammatory cytokines levels were significantly higher in the Control Group. Summary/Conclusion: Our findings suggest that prophylactic administration of defibrotide significantly reduces the incidence and severity of aGVHD, with a modification of patients’ cytokine pattern, strongly coherent with protective drug action. High costs currently limit the drug’s use. The positive impact on patient outcomes and the reduced long-term burdensome costs of GVHD and SOS should be considered.Keywords: Defibrotide, Acute graft-versus-host disease, Pediatric
P589: IMPLICATIONS OF REGISTRY DATA FOR ACUTE MYELOID LEUKEMIA (AML) TREATMENT AND CARE DURING THE COVID-19 PANDEMIC
Authors: Bart Scott, Mikkael Sekeres, Guillermo Garcia-Manero, David Grinblatt, Irene Degutis, Pavel Kiselev, Ali Mcbride, Willem Heydendael, Edward Yu, Gail Roboz
Journal: HemaSphere (2023)

Background: For patients (pts) with AML, timely treatment is critical. The COVID-19 pandemic broadly disrupted healthcare (eg, decreased blood donations), possibly causing delays in AML treatment and care. Aims: To determine the extent of the COVID-19 impact on AML, this analysis examines the effect of the pandemic on managing pts with AML in the Connect® Myeloid Registry (NCT01688011). Methods: The Registry is a large, US, multicenter, prospective, observational cohort study that includes newly diagnosed pts with AML aged ≥55 y. Pt characteristics (including assessment for transplant) were analyzed from December 2013 to February 2020 (from Registry opening to the start of the pandemic; Period 1), from March 2020 to May 2021 (during major healthcare disruptions; Period 2), and from June 2021 to January 2022 (resource stabilization and increased vaccine availability; Period 3); for the analysis of oral-containing medications, Period 1 began January 2019 to account for the FDA approval of venetoclax for AML in November 2018. Monthly COVID-19 incidence was calculated per weekly US government data (CDC COVID Data Tracker; 2023). Rates of visits (office, remote) and transfusions were calculated by monthly events/person-year to report event rates over time (sum of events of interest divided by the sum of follow-up for all pts within each month). Overall survival (OS) was estimated using the Kaplan-Meier method. Results: In this analysis, 650 pts were included in Period 1, 87 pts in Period 2, and 36 pts in Period 3; demographics and baseline characteristics were balanced across periods. Prior to the COVID-19 pandemic (Period 1), 25.1% of pts were not assessed for transplant; however, after the onset of the pandemic, this increased (45.5% and 44.4% in Periods 2 and 3, respectively). When monthly US COVID-19 cases increased, in-person visits and transfusion rates generally decreased in the Registry (Figure). The proportion of pts receiving oral-containing induction regimens was 49.4% (40/81) in Period 1 and 50.6% (44/87) in Period 2, with a slight increase to 63.9% (23/36) in Period 3. No significant differences in median OS by period were observed (Period 1 vs Period 2: 14.6 vs 13.7 mo, hazard ratio [HR] [95% CI], 0.90 [0.67-1.21], P = 0.47; Period 1 vs Period 3: 14.6 vs 17.6 mo, HR [95% CI], 0.74 [0.43-1.25], P = 0.26). Summary/Conclusion: In this analysis of pts with AML in the real-world setting, a pattern of increased COVID-19 cases in the US was accompanied by fewer transfusions, fewer in-person visits, and fewer assessments for stem cell transplantation; this pattern was particularly prominent in the initial months after onset of the pandemic without a significant impact on OS.Keywords: AML, Transfusion, COVID-19, Survival
PB1895: CHARACTERISTICS AND OUTCOME OF PEADIATRIC ACUTE PROMYELOCYTIC LEUKEMIA IN SOUTHERN TUNISIA
Authors: Asma Koubaa, Olfa Kassar, Maha Charfi, Faten Kallel, Taicir Rekik, Yousra Fakhfakh, Imen Frikha, Imen Ben Amor, Latifa Khalifa, Rahma Mallek, Moez Medhaffer, Sondes Hdiji, Hela Mnif, Moez Elloumi
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: Acute promyelocytic leukemia (APL) in children is rare, 5-10% of peadiatric acute myeloid leukemia. Aims: In this study, we present clinical and biological characteristics and outcome of children with APL. Methods: Our study was retrospective. It concerned all children, under 20 years, with the diagnosis of APL and followed in the hematology department of Hedi Chaker Hospital Sfax, from January 2000 until December 2019. The diagnosis of APL is based on morphological, cytogenetic and molecular study. The specific treatment is similar to that of the French protocol APL93 until 2013, and then similar to that of Spanish protocol LPA2005 since January 2014. We evaluated complete remission rate, death rate and overall survival (Kaplan-Meier). Results: We collected 20 patients with APL under 20 years, among 97 children with acute myeloid leukemia (20%). It was 12 boys and 8 girls, with sex ratio 1,5. The median age was 12 years. Hemorrhage syndrome au diagnosis was present in 80% of cases. The average white blood cell count was 18360/mm3. Hyperleukocytosis (GB> 10000/ mm3) was noted in 35% of cases. Disseminated intravascular coagulation (DIC) was founded in the majority of cases (95% of cases). Fifteen patients had the t(15,17), and three patients had additional cytogenetic abnormalities. Tow patients had a normal karyotype with positif PML-RARA transcript. Tow children died before treatment with hemorrhage. Four children died during the induction course and before evaluation. Complete remission was obtained in 13 patients (73% of the evaluable patients and 93% of the treated patients) and one patient failure (7%). This child was in CR after 2nd induction course. A late bone marrow relapse was observed in 2 patients (14%), after an average period of 45 months. After a median follow-up of 49 months, overall survival and event-free survival are 70% and 60%, respectively, and relapse-free survival is 79%. Summary/Conclusion: In our series, peadiatric APL (20%) is more frequently than that reported in the literature (5-10%). Clinical and biological characteristics are similar than that noted in the literature. However, hyper-leukocyte forms and early death rate were higher. RC rate, overall survival and event free survival were lower than that reported in the literature, could be explained by the higher hyper-leukocyte forms and early death rate. Keywords: APL, Pediatric